Review Article - International Journal of Respiratory Medicine (2021) Volume 6, Issue 1

The possible therapeutic options against COVID-19.

¹School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China

²Kaifeng Key Laboratory for Infectious Diseases and Biosafety, School of Basic Medical Science, Henan University, Kaifeng, Henan, China

³Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan China

⁴Department of Imaging and Nuclear Medicine, First Affiliated Hospital of Henan University School of Medicine, Kaifeng, Henan, China

⁵School of Stomatology, Henan University, Kaifeng, Henan, China

*Corresponding Author:

Dong-dong Wu and Xi Ying Ji
Henan International Joint Laboratory for Nuclear Protein Regulation
Henan University
Kaifeng, Henan 475004, China
E-mail: dongyangwu2007@sina.com

Accepted on September 20, 2021

Citation: Kombo AF, Ren ZG, Wang DY, et al. The possible therapeutic options against COVID-19. 2021: 6(1): 1-5.

Abstract

Aim: COVID-19 by SARS-CoV-2 is among the severe respiratory disease to be witnessed to date. SARS-Cov-2 brought about which is caused therapeutic difficulties all over the globe. The aim of this review is to evaluate the best possible therapeutic options to tackle the Novel Coronavirus related disease.

Method: Relevant published studies with keywords such as COVID-19 therapy, Sars-Cov-2 treatment and Novel Coronavirus antiviral therapy were extracted from different scientific journals and studied carefully.

Results: Some antiviral drugs, traditional Chinese medicine, immuno modulator drugs and quinoline have shown therapeutic abilities against Sars-Cov-2. However, tocilizumab and remdesvir have shown superiority over other groups of drugs.

Conclusion: Tocilizumab, an immuno modulator drug and viral protease inhibitor remdesivir have shown high efficacy against new coronavirus which raise the necessity for more research about these drugs.

Keywords

COVID-19, SARS-Cov-2, Tocilizumab, Remdesivir, Quinoline, Cytokines.

Introduction

Over decades, the world has witnessed the outbreak of Coronaviruses diseases such as Severe Acute Respiratory Syndrome (SARS) with the first case witnessed in Guangdong Province, Southern China in 2002 and identified as SARS-CoV in 2003 [1-3] Middle East Respiratory Syndrome (MERS) with the first case witnessed in Saudi Arabia in April 2002 [4-6] and Severe Acute Respiratory Syndrome Coronavirus-2 (Sars- CoV-2) which causes Coronavirus Disease-2019 (COVID-19) with the first case witnessed in Wuhan, China in December 2019 [7-10]. Coronaviruses are enveloped non-segmented positivesense RNA viruses belonging to the family Corona viridae and the order Nidovirales and broadly distributed in humans and other mammals [11-14]. Since the outbreak of first case of COVID-19 in December 2019 the scientists all over the world have been busy in conducting research for possible treatment and vaccine. To date there is neither treatment nor vaccine against coronavirus [15-17]. The novel coronavirus outbreak in December 2019 caused mass panic all over the world since this new strain of coronavirus is by comparison very deadly than the former strains [18]. Clinically, COVID-19 patients manifest with high grade fever, anorexia, shortness of breath, dry cough and fatigue [19-21]. Laboratory investigation reveals increased levels of neutrophil, Aspartate Aminotransferase (AST), Lactate Dehydrogenase (LDH) and C-reactive protein and decreased level of albumin and platelets [22-24]. Image studies reveal massive pleural effusion, Ground-Grass Opacities (GGO) and ground-glass opacity with consolidation [25].

This new strain is widely distributed all over the world regardless of the climate, geographical location or gender but according to the data, COVID-19 affects more elder than children [26]. This has raised the alarm for urgency in finding the possible therapy as soon as possible. The WHO have proposed social distancing, frequent hand washing, use of sanitizers and use of masks as possible preventive measures which if followed properly may lower the rate of transmission from person to another because the virus spread by cross contamination and aerosols [27]. But these measures are aimed at prevention only. It became necessary to find the proper cure of this disease as soon as practicable in order to save lives. So many scientists are working day and night to find the permanent solution to this deadly disease. This review summarizes the therapeutic possibilities of ongoing drugs trials.

Literature Review

Drugs investigated for treatment of COVID-19 in clinical trials/ in vivo studies

Tocilizumab - An IL-6r antagonist: Pathological studies done on people suffered from COVID-19 showed bilateral diffuse alveolar injury with cytomyxoid fibroma exudate [28]. Another study also showed evident desquamation of pneumocytes, hyaline membrane formation and pulmonary edema. This signifies that the patients had cytokine storm secondary to Cytokine Releasing Syndrome (SRS). This happens when Innate and adaptive immune systems are activated after the SARSCov- 2 bind to the alveolar epithelial cells in the lungs, resulting in the release of large number of cytokines such as IL-6. This causes increased vascular permeability which in turn results in the infiltration of fluids in the alveolar spaces [29]. Without intervention, this may result in acute respiratory failure and ultimately death. Hence, the immunosuppressive medication which is actually the IL-6 antagonist such as Tocilizumab may be of greater importance in the interference of inflammatory response which reverses the vascular permeability and easing the breathing problems [30]. Another study shows that, in the patients with COVID-19, there is large number of T cells and monoclonal macrophages that means SARS-Cov-2 activates the inflammatory response [31]. This in turn activates the cytokines such as IL-6 which binds to the IL-6 receptors in the target cells. The result is Cytokines storm and severe inflammatory response in lungs and other tissues. Because Tocilizumab is recombinant humanized anti-human IL-6 monoclonal antibody, it can prevent the binding process of IL-6 to its receptors and ultimately prevent the immune damage to the target cells hence alleviate the inflammatory response [32,33]. Another evidence is the case of 60years old Wuhan resident who was under treatment of Multiple Myeloma (MM) for more than two years. He experienced respiratory problems and on admission, was diagnosed with COVID-19. His CT scan revealed bilateral multiple ground-glass opacities and pneumatocele. His laboratory studies revealed increased serum IL-6. The patient was given intravenous Tocilizumab 8 mg/kg once a day and the symptoms disappeared and the laboratory studies also showed the decreased level of IL-6 within 10 days [34]. In the study done by Capra R, et al. [8], tocilizumab showed great efficacy against Coronavirus after [35] patients with confirmed to be affected by COVID-19 treated by a single dose of 400 mg intravenously and other 27 were given 324 mg tocilizumab subcutaneous once 8. Mihai and colleagues reported 57 years old WHO Grade I obese female diagnosed with systemic sclerosis interstitial lung disease (SSc-ILD) and type 2 diabetic was treated with tocilizumab for the SSc-ILD. She was diagnosed with mild COVID-19 and discharged home with symptomatic treatment only and was declared COVID-19 free 10 days later. In a study reported from Barcelona, 58 Covid-19 patients were given tocilizumab and other received tocilizumab in combination with corticosteroids. 8 patients (13.8%) died. In this report, Campins L, et al. [6], advised that the timing on when to initiate the immunomodulators to the Covid-19 patients are vital 6.

Tocilizumab, apart from being effective in fighting the cytokine storms with good efficacy, it also has superiority status in safety too.

Chloroquine/hydroxychloroquine-Theglycosylation inhibitor: Known for many years for its role as treatment and prophylaxis against malaria, the 9-aminoquinoline known as chloroquine has shown great efficacy in curing viral infections by inhibiting the viral replication processes [36,37]. This is done by altering the required pH Level inside the target cells. Viruses such as coronaviruses, flaviviruses and retroviruses need certain levels of pH in some steps of their replication. By altering the pH within the target cells, Chloroquine and Hydroxy-chloroquine has shown good ability to inhibit the viral replication and hence lower the viral load in the affected patient. The chloroquine and its hydroxy-analogue, hydroxychloroquine are basically weak bases. This property affects the acidic vesicles leading to dysfunction of some enzymes. Since they are positively charged, chloroquine and hydroxychloroquine cannot cross the plasma membrane but only its non-protonated portion can enter the intracellular compartment. According to the Henderson-Hesselbach law, non-protonated molecules can become protonated once enters the intracellular membrane since it is inversely proportional to the pH. When enters intracellular compartment, it ultimately lowers the pH of the cells and hence inhibit the viral replication [38]. In a study conducted in China, chloroquine had demonstrated great efficacy in treating pneumonia caused by SARS-CoV-2. Studies revealed that the chloroquine has broad-spectrum antiviral activities since it can increase endosomal pH required for the virus to bind to the cells and also can interfere the glycosylation of cellular receptors of SARS-CoV. This ability of chloroquine and hydroxy-chloroquine can warrant their use against SARS-CoV-2 associated pneumonia [39]. However, it is highly recommended that, when taken concomitantly with azithromycin and oseltamivir, the high dosage of CQ should be avoided when treating critically ill COVID-19 patients due to its potential safety hazard. Hydroxy-chloroquine should not be used as post exposure prophylaxis against COVID-19 since has shown no efficacy against the individual with high-risk or moderate-risk exposure to COVID-194.

Traditional Chinese Herbal Medicine (CHM): According to study by Yu and collogues, Traditional Chinese Herbal Medicine have unique role in treating viral infections including COVID-19. The study showed that a non-cytotoxic concentration of astragalus polysaccharide can inhibit the expression of two early viral proteins, Zta and Rta in the Epstein-Burr Virus lytic cycle to exert an antiviral effect [40]. Other study revealed that two Chinese drugs, Forsythiae fructus and Lonicerae japonicae flos have an ability to combine with 3CLpro and ACE2 to work against COVID-1918. CHM can alleviate or prevent the respiratory infections by inhibiting respiratory pathogens [41,42]. In combination with western medicine, CHM can be used effectively in treating COVID-19 patients 39.

Yang and his colleagues studied in vivo use of Lianhua Qingwen capsules against Influenza B virus (IBV) in Mice in combination with oseltamivir. Their study revealed that, the combination of 200 mg/kg/day of Lianhua qingwen capsules with 2 mg/kg/day of oseltamivir reduce the infection of lungs by IBV45. In China, after the outbreak of Sars-Cov-2, some hospitals tried to use 6 g Lianhua qingwen granules three times a day in combination with western medicine to treat covid-19 and yielded good results.

Lopinavir/Ritonavir-The protease inhibitors: Ritonavir and Lopinavir are under the class of protease inhibitor antiviral drugs. They work by inhibiting the synthesis of protein needed by the viral replication in the host cells. They do so by blocking the actions of protease enzyme and results in the formation of defective viruses which are unable to infect the body cells [43-45]. So, by using these drugs in the earlier stage of the viral disease, we expect to block the viral replication and ultimately lower the viral load. But Cao and colleagues concluded that, Ritonavir-lopinavir combination has no benefits beyond standard care in treating COVID-19 adult patients.

Remdesivir-An adenosine nucleotide analogue: Remdesivir, a 1’-cyano-substituted adenosine nucleotide inhibitor that has broad-spectrum antiviral activity against RNA Viruses [46-48]. In a study done by Mulangu S, et al. [32], demonstrated good tolerance and positive effect of Remdesivir in the lowering the viral load as well as mortality rate on the patients affected by 2018 Ebola virus in the Democratic republic of Congo Table 1. In vitro study including primary human epithelial cells culture, Remdesivir, a nucleotide prodrug, GS-5734 showed that it can inhibit the replication of SARS-Cov and MERS-Cov35.

Table 1. Proposed doses for drugs investigated for the treatment of COVID-19 in clinical trials.

Since it is nucleoside analogue prodrug, Remdesivir can inhibit the viral RNA polymerases hence it can block the activity of SARS-CoV-2. In patients hospitalized for severe COVID-19, Remdesivir was given and yield a good result after 36 out of 53 (68%) patients had shown good clinical improvement.

Another case of 35-years old man who was diagnosed with COVID-19 on January 2020 in United States; The compassionate administration of Intravenous Remdesivir was done on hospitalization day 7 and yielded good result with no any adverse effect recorded.

Another evident study conducted in Italy on March, 2020 where the compassionate administration of 200 mg loading dose of Remdesivir followed by 100mg maintenance dose to the COVID-19 severely ill patients showed a good result. But few patients had multiple organ failure, cardiac problem such as torsade de pointes and QT Prolongation due to arrythmia and some had altered biochemical readings such as increased ALT and AST. Remdesivir which showed strong antiviral activity against MERS-CoV compared to Ropinavir/Litonavir can be used against Sars-CoV-2 as well since these viruses have the same origin and bear same characteristics.

Conclusion

Since Tocilizumab and Remdesivir have shown superiority against COVID-19 over other drugs discussed in this review, it is highly recommended that these two classes of drugs should be given priority on doing more research about them. Tocilizumab can block the inflammatory response induced by SARS-CoV-2 infection and hence prevent the vascular permeability which in turn prevents the pulmonary edema and Disseminated Intravascular Coagulation (DIC). Remdesivi in other hand can be used to block the viral replication. By so doing it will lower the viral load and make it easier for the natural immunity to fight the low dose of viruses. It is recommended that these drugs have to be used simultaneously in order to get the full benefits of them.

Acknowledgement

This review has full technical and administrative supports from Dong-Dong Wu and Xin-Ying Ji.

References

1. Agostini ML, Andres EL, Sims AC, et al. Coronavirus susceptibility to the antiviral Remdesivir (Gs-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. MBIO. 2018;9.
2. Boelaert JR, Piette J, Sperber K. The potential place of chloroquine in the treatment of HIV-1-infected patients. J Clin Virol. 2001;20:137-40.
3. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs. low doses of Chloroquine Diphosphate as adjunctive therapy for patients hospitalized with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) infection: A randomized clinical trial. JAMA Netw Open. 2020;3:e208857.
4. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of Hydroxy-chloroquine as Postexposure Prophylaxis for COVID-19. N Engl J Med. 2020.
5. Cai J, Sun W, Huang J, et al. Indirect virus transmission in cluster of COVID-19 Cases, wenzhou, china, 2020. Emerg Infect Dis. 2020;20:1343-1345.
6. Campins L, Boixeda R, Perez-Cordon L, et al. (2020) early tocilizumab treatment could improve survival among COVID-19 patients. Clin Exp Rheumatol 2020;38:578.
7. Cao B, Wang Y, Wen D, et al. A trial of Lopinavir-Ritonavir in adults hospitalized with severe COVID-19. N Engl J Med 2020; 382:1787-1799.
8. Capra R, De Rossi N, Mattioli F, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. Eur J Intern Med 2020;72:31-35.
9. Chen J. Pathogenicity and transmissibility of 2019-ncov-a quick overview and comparison with other emerging viruses. Microbes Infect 2020;22:69-71.
10. De Groot RJ, Baker SC, Baric RS, et al. Middle east respiratory syndrome coronavirus (mers-cov): announcement of the coronavirus study group. J Virol 2013;87:7790-7792.
11. Desjardins MR, Hohl A, Delmelle EM. Rapid surveillance of covid-19 in the united states using a prospective space-time scan statistic: detecting and evaluating emerging clusters. Appl Geogr. 2020;118:102202.
12. Drosten C, Günther S, Preiser W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med. 2003;348:1967-1976.
13. Durante-Mangoni E, Andini R, Bertolino L, et al. Early experience with Remdesivir in SARS-Cov-2 pneumonia. Infection 2020;1-4.
14. Ferreira DF, Santo MPE, Rebello MA, et al. Weak bases affect late stages of Mayaro virus replication cycle in vertebrate cells. J Med Microbiol. 2000;49:313-318.
15. Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med. 2020;18:164.
16. Gabay C, Emery P, Vollenhoven R, et al. Kavanaugh, Tocilizumab monotherapy vs. Adalimumab Monotherapy for treatment of rheumatoid arthritis (Adacta): A randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381:1541-1550.
17. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine Phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Bio Sci Trends. 2020;14:72-73.
18. Gao LQ, Xu J, Chen SD. In silico screening of potential Chinese herbal medicine against COVID-19 by targeting SARS-cov-2 3clpro and angiotensin converting enzyme II using molecular docking. Chin J Integr Med. 2020;26:527-532.
19. Gao Y, Yan L, Huang Y, et al. Structure of the RNA-dependent RNA polymerase from COVID-19 Virus. Science. 2020;368:779-782.
20. Grein J, Ohmagari N, Shin D, et al. Childs, and T. Flanigan, compassionate use of Remdesivir for patients with severe COVID-19. N Engl J Med. 2020;382:2327-2336.
21. Han R, Huang L, Jiang H, et al. Early clinical and CT manifestations of Coronavirus Disease 2019 (COVID-19) pneumonia. AJR Am J Roentgenol. 2020;1-6.
22. Holshue ML, DeBolt C, Lindquist S, K. et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382:929-936.
23. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, china. Lancet. 2020;395:497-506.
24. Kakimoto K, Kamiya H, Yamagishi T, et al. Initial investigation of transmission of COVID-19 among crew members during quarantine of a cruise ship - Yokohama, Japan, February 2020. MMWR Morb Mortal Wkly Rep. 2020;30:312-313.
25. Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med. 2003;348:1953-1966.
26. Liu M, Gao Y, Yuan Y, et al. Efficacy and safety of integrated traditional Chinese and Western medicine for Corona Virus Disease 2019 (COVID-19): A systematic review and meta-Analysis. Pharmacol Res. 2020;158:104896.
27. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395:565-574.
28. Marra MA, Jones SJ, Astell CR, et al. The genome sequence of the SARS-associated coronavirus. science. 2003;300:1399-1404.
29. Mihai C, Dobrota R, Schröder M, et al. COVID-19 in a patient with systemic sclerosis treated with tocilizumab for SSC-ILD. Ann Rheum Dis. 2020;79:668-669.
30. Mo P, Xing Y, Xiao Y, et al. Clinical characteristics of refractory COVID-19 pneumonia in wuhan, china. Clin Infect Dis. 2020.
31. Morawska L, Cao J. Airborne transmission of SARS-Cov-2: The world should face the reality. Environ Int. 2020;139:105730.
32. Mulangu S, Dodd LE, Davey TL, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019;381:2293-2303.
33. Ohkuma S, Poole B. Cytoplasmic vacuolation of mouse peritoneal macrophages and the uptake into lysosomes of weakly basic substances. J Cell Biol. 1981;90:656-664.
34. Paskaš S, Krajnović T, Basile MS, et al. Senescence as a main mechanism of ritonavir and ritonavir-no action against melanoma. Mol Carcinog. 2019;58:1362-1375.
35. Sheahan TP, Sims AC, Graham RL, et al. Broad-Spectrum antiviral Gs-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9.
36. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of Remdesivir and combination Lopinavir, Ritonavir, and Interferon Beta against Mers-Cov. Nat Commun. 2020;11: 222.
37. Su S, Wong G, Shi W, et al. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol. 2016;24:490-502.
38. Tchesnokov EP, Feng JY, Porter DP, et al. Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by Remdesivir. Viruses. 2019;11.
39. Wan S, Xiang Y, Fang W, et al. Clinical features and treatment of COVID-19 patients in Northeast Chongqing. J Med Virol. 2020;92:797-806.
40. Wang M, Cao R, Zhang L, et al. Remdesivir and Chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCov) in vitro. Cell Res. 2020;30:269-271.
41. Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004;136:95-103.
42. Wu J, Liu J, Zhao X, et al. Clinical characteristics of imported cases of COVID-19 in Jiangsu province: A multi-center descriptive study. Clin Infect Dis. 2020.
43. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with Tocilizumab, proc Natl Acad Sci USA. 2020;117:10970-10975.
44. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med.2020;8:420-422.
45. Yang C, Wang Y, He J, et al. Lianhua-Qingwen displays antiviral and anti-inflammatory activity and synergistic effects with oseltamivir against influenza b virus infection in the mouse model. Evid Based Complement Alternat Med. 2020;2020:3196375.
46. Yu S, Wang J, Shen H. Network pharmacology-based analysis of the role of traditional Chinese herbal medicines in the treatment of COVID-19. Ann Palliat Med. 2020;9:437-446.
47. Zhang C, Wu Z, Li JW, et al. Cytokine release syndrome in severe COVID-19: Interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55:105954.
48. Zhang X, Song K, Tong F, et al. First case of COVID-19 in a Patient with multiple myeloma successfully treated with tocilizumab. Blood Adv. 2020;4:1307-1310.